Previous work from our unit has shown that there is functional impairment in the skin microcirculation of the diabetic foot that prevents full vasodilation under conditions of stress or response to injury and thereby sets the stage for the development of foot ulceration and impedes wound healing. We now propose that similar changes exist in the muscle microcirculation of the diabetic foot and are contributing to the wound healing failure, in order to explore our hypothesis, we will employ new techniques to study prospectively the altered metabolic indices of muscle tissue, skin oxygenation and skin microcirculation at the foot level. The current proposal is strengthened by the fact that we are already conducting a clinical trial funded by the American Diabetes Association involving the long-term follow up of a cohort of diabetic neuropathic diabetic patients at risk of developing foot ulceration. We are following 150 diabetic patients at high risk of foot ulceration and are comparing them to diabetic patients not at risk and healthy control subjects for a period up to three years. One group of 25 non-neuropathic patients and one group of 25 healthy subjects wilt serve as controls. The endothelial function at the micro- and macro-circulation will be evaluated at baseline by employing state of the art non-invasive techniques. Biochemical markers of endothelial activation, such as von Willebrand factor (vWF), endothetin-1, Plasminogen Activator Inhibitor (PAl1), Tumor Necrosis Factor (TNFa), lnterleukin 6, C-Reactive Protein (CRP), Vascular Endothelial Growth Factor (VEGF) and cellular adhesion molecules (CAMs) will also be measured. This population will be followed for a period of three years and endothelial function will be examined periodically. The development of new ulcers and their failure to heal will be a major end-point. Our primary hypothesis of the current proposal is that vascular functional abnormalities in the macro- and microcirculation in the diabetic foot are involved in the development of foot ulceration and failure to heal the ulceration. We now propose to expand the scope of the study and investigate the muscle metabolism through Magnetic Resonance Spectroscopic (MRS) studies of the phosphorous metabolites, using the MRI technique known as rapid acquisition with relaxation enhancement (RARE), and the skin oxygen saturation, using Hyperspectral Imaging (HSl) at the foot level. We hypothesize, that the metabolism of the small muscle of the foot is indicative of the metabolism of the surrounding tissues, including skin and that it depends on intact microcirculatory physiology, Furthermore, the ratio of saturated/unsaturated hemoglobin and the total amount of hemoglobin at the skin level can be used as indexes of skin ischemia. Therefore, the combination of MRI RARE measurements and HIS will effectively identify patients at risk of foot ulceration and also predict failure to heal an ulcer.